We have shown that in mice, cocaine is metabolized, through nor-cocaine and N-hydroxy nor-cocaine (NHNC) to a hepatotoxic metabolite. The relationship of NHNC metabolism to liver damage after the acute and chronic administration of cocaine will be examined in mice, rats and hamsters. Mice will be pretreated with inducers and inhibitors of microsomal mixed function oxidases. The content of cytochromes P450 and P448 will be determined, as well as the activity of drug metabolizing enzymes including N- and O- demethylases and aniline hydroxylase. The in vitro formation and disappearance of NHNC will be determined by high pressure liquid chromatography with an electrochemical detector. This system will also be used to isolate and identify adducts and breakdown products of NHNC. Several analogues of NHNC will be synthesized and tested for hepatotoxicity, as measured by increased levels of serum transaminases and histological damage. The covalent binding of metabolites of tritiated nor-cocaine and NHNC to proteins nucleic acids and sulfhydryl compounds will be measured in vivo and in vitro. Such binding will be correlated with sex, strain and species differences in liver damage, as well as with the activity of microsomal enzymes. Morphine-induced hepatotoxicity in mice is characterized by fatty infiltration and elevation of serum transaminases. We will examine the effect of inducers and inhibitors of microsomal cytochrome systems on liver damage after morphine. The hepatotoxic response to intracerebral injections of morphine will be measured in an attempt to determine whether the liver damage is centrally mediated. Combinations of cocaine and morphine will be administered to untreated mice and to animals that have been induced by pretreatment with phenobarbital or ethanol. The aim of these experiments is to assess potential liver damage from polydrug abuse.